Differential outcome of MEK1/2 inhibitor-platinum combinations in platinum-sensitive and -resistant ovarian carcinoma cells

Giacomo Cossa, Cinzia Lanzi, Giuliana Cassinelli, Nives Carenini, Noemi Arrighetti, Laura Gatti, Elisabetta Corna, Franco Zunino, Nadia Zaffaroni, Paola Perego

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Deregulated pro-survival signalling plays a role in ovarian carcinoma drug resistance. Here, we show that cisplatin or oxaliplatin in combination with the MEK1/2 inhibitor CI-1040 resulted in a synergistic effect associated with enhanced apoptotic response in platinum-sensitive cells. The drug combinations were additive in platinum-resistant cells exhibiting increased phospho-ERK1/2, down-regulation of apoptosis-related factors (BAX, PUMA, FOXO1) and of phosphatases inhibiting ERK1/2 (DUSP5, DUSP6). Consistently, FOXO1 knockdown in sensitive cells reduced the efficacy of the combination treatment. Pharmacological targeting of ERK1/2 pathway increases cell sensitivity to platinum compounds by interfering with multiple events, ultimately favouring apoptosis induction in selected molecular backgrounds.

Original languageEnglish
Pages (from-to)212-224
Number of pages13
JournalCancer Letters
Volume347
Issue number2
DOIs
Publication statusPublished - Jun 1 2014

Fingerprint

Platinum
Carcinoma
oxaliplatin
Platinum Compounds
Apoptosis
MAP Kinase Signaling System
Drug Combinations
Phosphoric Monoester Hydrolases
Drug Resistance
Cisplatin
Down-Regulation
Pharmacology

Keywords

  • Drug resistance
  • FOXO1
  • MEK inhibitors
  • Ovarian carcinoma
  • Platinum compounds

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Differential outcome of MEK1/2 inhibitor-platinum combinations in platinum-sensitive and -resistant ovarian carcinoma cells. / Cossa, Giacomo; Lanzi, Cinzia; Cassinelli, Giuliana; Carenini, Nives; Arrighetti, Noemi; Gatti, Laura; Corna, Elisabetta; Zunino, Franco; Zaffaroni, Nadia; Perego, Paola.

In: Cancer Letters, Vol. 347, No. 2, 01.06.2014, p. 212-224.

Research output: Contribution to journalArticle

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AU - Cossa, Giacomo

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AU - Cassinelli, Giuliana

AU - Carenini, Nives

AU - Arrighetti, Noemi

AU - Gatti, Laura

AU - Corna, Elisabetta

AU - Zunino, Franco

AU - Zaffaroni, Nadia

AU - Perego, Paola

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